Age-related maculopathy (also known as age-related macular degeneration) is a leading cause of central blindness in the elderly population and numerous studies support a strong underlying genetic component to this complex disorder. Genome-wide linkage scans using large pedigrees, affected sib pairs, and more recently, discordant sib pairs, have identified a number of potential susceptibility loci (Klein et al. 1998 Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Archives of Ophthalmology 116:1082-1088; Weeks et al. 2000 A full genome scan for age-related maculopathy. Human Molecular Genetics 9:1329-1349; Majewski et al. 2003 Age-related macular degeneration—a genome scan in extended families. Am J Hum Genet 73:540-550; Schick et al. 2003 A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 72:1412-1424; Seddon et al. 2003 A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 73:780-790; Abecasis et al. 2004—Age-related macular degeneration: a high-resolution genome scan for susceptibility Loci in a population enriched for late-stage disease. Am J Hum Genet 74:482-494; Iyengar et al. 2004 Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 74:20-39; Kenealy et al. 2004 Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26. Mol Vis 10:57-61; Schmidt et al. 2004 Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12. BMC Genet 5:18; Weeks et al. 2004 Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am J Hum Genet 75:174-189; Santangelo et al. 2005 A Discordant Sib-Pair Linkage Analysis of Age-Related Macular Degeneration. Ophthalmic Genetics 26:61-68). Genome-wide linkage screen strongly implicated the 10q26 region as likely to contain an age-related macular degeneration (AMD) gene (Weeks et al. 2004); this region has also been supported by many other studies and is the top-ranked region in a recent meta analysis (Fisher et al. 2005 Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet. 2005 Aug. 1; 14(15):2257-64). Recently, three papers appeared in Science (Edwards et al. 2005 Complement Factor H Polymorphism and Age-Related Macular Degeneration. Science 308, 421-424; Haines et al. 2005 Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration. Science 308, 419-421. Klein et al. 2005 Complement Factor H Polymorphism in Age-Related Macular Degeneration. Science 308, 385-389) identifying an allelic variant in complement factor H (CFH) as responsible for the linkage signal seen on Chromosome 1 and accounting for a significant attributable risk for ARM in both familial and sporadic cases. These findings have been confirmed (Conley et al. 2005 Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum Mol Genet 14: 1991-2002; Hageman et al. (2005a) From The Cover: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227-7232; and Zareparsi et al. 2005a Strong Association of the Y402H Variant in Complement Factor H at 1q32 with Susceptibility to Age-Related Macular Degeneration. Am J Hum Genet 77:149-53). CFH has been previously suspected of playing a role in ARM due to the work of Hageman and Anderson (Hageman and Mullins 1999 Molecular composition of drusen as related to substructural phenotype. Molecular Vision 5:28; Johnson et al. 2000 A potential role for immune complex pathogenesis in drusen formation. Experimental Eye Research 70:441-449 Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Experimental Eye Research 73:887-896; Mullins et al. 2000 Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB Journal 14:835-846; Hageman et al. 2001 An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Progress in Retinal & Eye Research 20:705-732; Johnson et al. 2001), who have shown that the subretinal deposits (drusen) that are observed in many ARM patients contain complement factors. However until other genes that contribute to ARM are identified, CFH remains an isolated piece of the puzzle, implicating the alternative pathway and inflammation as part of the ARM pathogenesis, but failing to account for the unique pathology that is observed in the eye.